Pierre Beaulieu

Behavioral, pharmacological and molecular characterization of the saphenous nerve partial ligation: A new model of neuropathic pain

The saphenous partial ligation (SPL) model is a new, easily performed, rodent model of neuropathic pain that consists of a unilateral partial injury to the saphenous nerve. The present study describes behavioral, pharmacological and molecular properties of this model. Starting between 3 and 5 days after surgery, depending on the modality tested, animals developed clear behaviors indicative of neuropathic pain such as cold and mechanical allodynia, and thermal and mechanical hyperalgesia compared with naive and sham animals. These pain behaviors were still present at 1 month. Signs of allodynia also extended to the sciatic nerve territory. No evidence of autotomy or bodyweight loss was observed. Cold and mechanical allodynia but not thermal and mechanical hyperalgesia was reversed by morphine (4 mg/kg i.p.). The cannabinoid receptor agonist WIN 55,212-2 (5 mg/kg i.p.) improved signs of allodynia and hyperalgesia tested except for mechanical hyperalgesia. Gabapentin (50 mg/kg i.p.) was effective against cold and mechanical allodynia but not hyperalgesia. Finally, amitriptyline (10 mg/kg i.p.) failed to reverse allodynia and hyperalgesia and its administration even led to hyperesthesia. Neurobiological studies looking at the expression of mu opioid receptor (MOR), cannabinoid CB(1) and CB(2) receptors showed a significant increase for all three receptors in ipsilateral paw skin, L3-L4 dorsal root ganglia and spinal cord of neuropathic rats compared with naive and sham animals. These changes in MOR, CB(1) and CB(2) receptor expression are compatible with what is observed in other neuropathic pain models and may explain the analgesia produced by morphine and WIN 55,212-2 administrations. In conclusion, we have shown that the SPL is an adequate model that will provide a new tool for clarifying peripheral mechanisms of neuropathic pain in an exclusive sensory nerve.

Effects of nabilone, a synthetic cannabinoid, on postoperative pain

PurposeCannabinoids have been shown to have analgesic properties in animal studies, but a potential role for these drugs in acute pain management has not been established. It was hypothesized that nabilone, an oral cannabinoid synthetic tetrahydrocannabinol analogue, decreases morphine consumption, pain scores, nausea and vomiting following major surgery.MethodsA double-blind, randomized, placebo-controlled, parallel-group pilot trial compared the effects of two different doses, 1 mg (n = 11) and 2 mg (n = 9) of nabilone, ketoprofen 50 mg (n = 11) or placebo (n = 10), given at eight-hour intervals for 24 hr. Outcomes included morphine consumption, pain scores and emesis after major surgery. Secondary outcomes included patient tolerability of the study medication.ResultsForty-one patients (mean age 52 ± 2 yr) undergoing gynecologic (46%), orthopedic (44%), or other (10%) surgery were recruited. Cumulative 24-hr morphine consumption was not different between the four groups, but pain scores at rest and on movement were significantly higher in the 2 mg nabilone group compared to the other groups. There were no significant differences between groups with respect to episodes of nausea and vomiting, quality of sleep, sedation, euphoria, pruritus, or the number and severity of adverse events. No serious adverse event was recorded.ConclusionsContrary to the main hypothesis, high dose nabilone in the presence of morphine patient controlled analgesia is associated with an increase in pain scores in patients undergoing major surgery.RésuméObjectifLes propriétés analgésiques des cannabinoïdes ont été démontrées chez des animaux, mais leur rôle possible sur le contrôle de la douleur aiguë n’a pas été établi. Notre hypothèse voulait que la nabilone, analogue synthétique oral du cannabinoïde tétrahydrocannabinol, diminue la consommation de morphine, les scores de douleur, les nausées et les vomissements à la suite d’une opération chirurgicale majeure.MéthodeDans une étude pilote de groupes parallèles, randomisée, à double insu et contrôlée contre placebo, les effets de deux doses de nabilone, 1 mg (n = 11) et 2 mg (n = 9), de 50 mg de kétoprofène (n = 11) ou d’un placebo (n = 10), administrés à 8 h d’intervalle pendant 24 h, ont été comparés. La consommation de morphine, les scores de douleur et les vomissements ont été notés après une chirurgie majeure. Les effets de la médication sur le patient étaient également étudiés.RésultatsQuarante et un patients (moyenne d’âge de 52 ± 2 ans) subissant une intervention gynécologique (46 %), orthopédique (44 %) ou autre (10 %) ont été recrutés. La consommation cumulative de morphine sur 24 h était similaire dans les quatre groupes, mais les scores de douleur au repos et au mouvement ont été significativement plus élevés dans le groupe nabilone 2 mg. Aucune différence intergroupe significative n’est apparue quant aux épisodes de nausées et de vomissements, la qualité du sommeil, la sédation, l’euphorie, le prurit ou le nombre et la sévérité des événements indésirables. Aucun incident sérieux n’a été enregistré.ConclusionContrairement à notre hypothèse, une forte dose de nabilone, en présence de morphine administrée comme analgésie auto-contrôlée, est associée à une hausse des scores de douleur chez les patients qui subissent une chirurgie majeure.

The antinociceptive effects of intraplantar injections of 2‐arachidonoyl glycerol are mediated by cannabinoid CB2 receptors

2‐arachidonoyl glycerol (2‐AG) is an endogenous cannabinoid with central antinociceptive properties. Its degradation is catalysed by monoacylglycerol lipase (MGL) whose activity is inhibited by URB602, a new synthetic compound. The peripheral antinociceptive effects of 2‐AG and URB602 in an inflammatory model of pain are not yet determined. We have evaluated these effects with and without the cannabinoid CB1 (AM251) and CB2 (AM630) receptor antagonists.

Local interactions between anandamide, an endocannabinoid, and ibuprofen, a nonsteroidal anti-inflammatory drug, in acute and inflammatory pain

Abstract Anandamide, an endocannabinoid, is degraded by the enzyme fatty acid amide hydrolase which can be inhibited by nonsteroidal anti‐inflammatory drugs (NSAIDs). The present work was designed to study the peripheral interactions between anandamide and ibuprofen (a non‐specific cyclooxygenase inhibitor) in the rat formalin test. We first determined the ED50 for anandamide (0.018 &mgr;g ± 0.009), ibuprofen (0.18 &mgr;g ± 0.09), and their combination (0.006 &mgr;g ± 0.002). Drugs were given 15 min before a 2.5% formalin injection into the dorsal surface of the right hind paw. Results were analyzed using isobolographic analysis. The antinociceptive interaction between anandamide and ibuprofen was synergistic. To further investigate the mechanisms by which the combination of anandamide with ibuprofen produced their antinociceptive effects, we used specific antagonists for the cannabinoid CB1 (AM251; 80 &mgr;g) and CB2 (AM630; 25 &mgr;g) receptors. We demonstrated that the antinociceptive effects of ibuprofen were not antagonized by either AM251 or AM630 and that those of anandamide were antagonized by AM251 but not by AM630. The synergistic antinociceptive effects of the combination of anandamide with ibuprofen were completely antagonized by AM251 but only partially inhibited by AM630. In conclusion, locally (hind paw) injected anandamide, ibuprofen or combination thereof decreased pain behavior in the formalin test. The combination of anandamide with ibuprofen produced synergistic antinociceptive effects involving both cannabinoid CB1 and CB2 receptors. Comprehension of the mechanisms involved needs further investigation.

Antihyperalgesic effects of local injections of anandamide, ibuprofen, rofecoxib and their combinations in a model of neuropathic pain

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit fatty acid amidohydrolase (FAAH), the enzyme responsible for the metabolism of anandamide, an endocannabinoid. The analgesic interactions between anandamide (0.01 microg), ibuprofen (0.1 microg) and rofecoxib (0.1 microg) or their combinations administered locally in the hind paw of neuropathic rats were investigated together with the effects of specific antagonists for the cannabinoid CB(1) (AM251; 80 microg) and CB(2) (AM630; 25 microg) receptors. Mechanical allodynia and thermal hyperalgesia were evaluated in 108 Wistar rats allocated to: (1-4) NaCl 0.9%; anandamide; ibuprofen; rofecoxib; (5-6) anandamide+ibuprofen or rofecoxib; (7-8) AM251 or AM630; (9-10) anandamide+AM251 or AM630; (11-12) ibuprofen+AM251 or AM630; (13-14) rofecoxib+AM251 or AM630; (15-16) anandamide+ibuprofen+AM251 or AM630; (17-18) anandamide+rofecoxib+AM251 or AM630. Drugs were given subcutaneously in the hind paw 15min before pain tests. Anandamide, ibuprofen, rofecoxib and their combinations significantly decreased mechanical allodynia and thermal hyperalgesia with an ED(50) of 1.6+/-0.68ng and 1.1+/-1.09 ng for anandamide, respectively. The effects of NSAIDs were not antagonized by AM251 or AM630 but those of anandamide were inhibited by AM251 but not by AM630. In conclusion, locally injected anandamide, ibuprofen, rofecoxib and their combinations decreased pain behavior in neuropathic animals. Local use of endocannabinoids to treat neuropathic pain may be an interesting way to treat this condition without having the deleterious central effects of systemic cannabinoids.

Recent Advances in the Pharmacological Management of Pain

Pain is an unpleasant sensation that originates from ongoing or impending tissue damage. Management of different types of pain (acute, postoperative, inflammatory, neuropathic or cancer) is the most frequent issue encountered by clinicians and pharmacological therapy is the first line of approach for the treatment of pain. This review presents and discusses recent clinical advances regarding both the improvements in delivery of analgesic drugs and improvements in the design of analgesic molecules. The new modalities of administration of analgesics used in the clinic are reviewed, including skin patches, oral and mucosal sprays, transdermal delivery systems and intranasal administration. New insights are then presented on standard drugs used to relieve pain, such as opioids (including tramadol), NSAIDs including selective cyclo-oxygenase-2 inhibitors, paracetamol (acetaminophen), local anaesthetics and adjuvant analgesics such as antidepressants, anticonvulsants (gabapentin and pregabalin), cannabinoids, ketamine and others (e.g. nefopam). Although the understanding of pain mechanisms has improved significantly recently, much more is yet to be discovered and awaited. Broadening of our knowledge is needed to improve basic and clinical research in this field in order to better alleviate pain in millions of people

Modulation of the anti-nociceptive effects of 2-arachidonoyl glycerol by peripherally administered FAAH and MGL inhibitors in a neuropathic pain model

There are limited options for the treatment of neuropathic pain. Endocannabinoids, such as anandamide and 2‐arachidonoyl glycerol (2‐AG), are promising pain modulators and there is recent evidence of interactions between anandamide and 2‐AG biosynthesis and metabolism. It has been clearly demonstrated that 2‐AG degradation is mainly catalysed not only by monoacylglycerol lipase (MGL) but also by a fatty acid amide hydrolase (FAAH). Inhibitors specifically targeting these two enzymes have also been described: URB602 and URB597, respectively. However, the anti‐nociceptive effects of the combination of peripherally injected 2‐AG, URB602 and URB597 in a neuropathic pain model have not yet been determined. This was performed in the presence or absence of cannabinoid CB1 (AM251) and CB2 (AM630) receptor antagonists.

Characterization of chronic constriction of the saphenous nerve, a model of neuropathic pain in mice showing rapid molecular and electrophysiological changes

Neuropathic pain is one of the most inextricable problems encountered in clinics, because few facts are known about its etiology. Nerve injury often leads to allodynia and hyperalgesia, which are symptoms of neuropathic pain. The aim of this study was to understand some molecular and electrophysiological mechanisms of neuropathic pain after chronic constriction of the saphenous nerve (CCS) in mice. After surgery, CCS mice displayed significant allodynia and hyperalgesia, which were sensitive to acute systemic injection of morphine (4 mg/kg), gabapentin (50 mg/kg), amitriptyline (10 mg/kg), and the cannabinoid agonist WIN 55,212‐2 (5 mg/kg). These behavioral changes were accompanied after surgery by an increase of c‐Fos expression and by an overexpression of μ‐opioid and cannabinoid CB1 and CB2 receptors in the spinal cord and the dorsal hind paw skin. In combination with the skin‐nerve preparation, this model showed a decrease in functional receptive fields downstream to the injury and the apparition of A‐fiber ectopic discharges. In conclusion, CCS injury induced behavioral, molecular, and electrophysiological rearrangements that might help us in better understanding the peripheral mechanisms of neuropathic pain. This model takes advantage of the possible use in the future of genetically modified mice and of an exclusively sensory nerve for a comprehensive study of peripheral mechanisms of neuropathic pain.

Progress in natural product chemistry by the chiron and related approaches - synthesis of avermectin B 1a

A strategy for the total synthesis of avermectin Bla is presented based on aspects of the utilization of chirons derived from naturally—occurring starting materials, asymmetric synthesis, and computer—assisted stereochemical analysis. INTRODUCTION Over the years, Nature has been a generous and abundant supplier of products to the community of chemists and biologists. Through their separate and combined ingenuity, these groups of scientists have exploited Natures gifts in many ways, the most dramatic of which has been in medicinal applications, hence directly related to our present—day quality of life. A number of life—saving drugs have their direct origins in Nature. Many others are the result of chemical modification of existing natural products, or synthetic endeavors. While the supply of new natural products and the emergence of novel structural types is ever so active, only a select few become serious candidates for in depth biological evaluation. Of these, perhaps a disappointingly small percentage are successful in more rigorous pharmacological and therapeutic scrutiny. Finally, after years of study on many fronts, there may emerge a product that combines the many features that constitute a novel drug, be it for human, animal or related use. One such group of products is the avermectins consisting of isomeric macrocyclic lactones of unique structure (ref. 1) and exhibiting potent anthelmintic activity (ref. 1, 2). The most active component, avermectin Bla has been shown to have the structure shown in Figure 1, as a result of elegant structure elucidation studies involving degradative and X—ray crystallographic studies (ref. 3). The avermectins, consisting of several components which

Peptidic regulation of heart rate and interactions with the autonomic nervous system

Autonomic influences on the heart rate have been the subject of intense research for many decades and are classically devoted to the sympathetic and parasympathetic systems. However, developments over the past few years in our knowledge of the organization of the autonomic nervous system have led to the conclusion that in addition to the classical transmitters, peptidic transmitters are clearly present and have direct or indirect actions on cardiac conduction. Neuropeptides have been found to collocate with each other or with classical transmitters, thereby increasing the variety of chemical signals that a neuron can utilize to communicate with other cells. Neuropeptides can act as neurotransmitters, neuromodulators or neurohormones. Some are produced in endocrine glands and circulate as hormones, while others are contained in cardiac myocytes, neurons, or endothelial cells in proximity to the sinoatrial node and can therefore act in a paracrine or autocrine way on the pacemaker cells to modulate heart frequency. There is evidence supporting such a role, especially for locally situated neuropeptide Y, vasoactive intestinal peptide, calcitonin gene-related peptide, substance P, angiotensin II, natriuretic peptides, endothelins and possibly many others. The role of the peptidic neurotransmitters in the conduction system should not be exaggerated. Nevertheless, neuropeptides certainly represent a new category of neurotransmitters forming a third component of the autonomic nervous system and may have complex actions with potential therapeutic implications in man.